title: Inhibition of weak-affinity epitope-IgE interactions prevents mast cell degranulation.
abstract: Development of specific inhibitors of allergy has had limited success, in part, owing to a lack of experimental models that reflect the complexity of allergen-IgE interactions. We designed a heterotetravalent allergen (HtTA) system, which reflects epitope heterogeneity, polyclonal response and number of immunodominant epitopes observed in natural allergens, thereby providing a physiologically relevant experimental model to study mast cell degranulation. The HtTA design revealed the importance of weak-affinity epitopes in allergy, particularly when presented with high-affinity epitopes. The effect of selective inhibition of weak-affinity epitope-IgE interactions was investigated with heterobivalent inhibitors (HBIs) designed to simultaneously target the antigen- and nucleotide-binding sites on the IgE Fab. HBI demonstrated enhanced avidity for the target IgE and was a potent inhibitor of degranulation in vitro and in vivo. These results demonstrate that partial inhibition of allergen-IgE interactions was sufficient to prevent mast cell degranulation, thus establishing the therapeutic potential of the HBI design.
authors.affiliation: Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Handlogten
authors.forename: Tanyel
authors.initials: T
authors.lastname: Kiziltepe
authors.forename: Ana P
authors.initials: AP
authors.lastname: Serezani
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Basar
authors.initials: B
authors.lastname: Bilgicer
mesh_terms: D000485:Allergens / Q000737:chemistry / Q000276:immunology; D000818:Animals; D001665:Binding Sites; D015550:Cell Degranulation / Q000502:physiology*; D000939:Epitopes / Q000737:chemistry / Q000378:metabolism*; D007073:Immunoglobulin E / Q000378:metabolism*; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D010323:Passive Cutaneous Anaphylaxis / Q000276:immunology; D011487:Protein Conformation; D015202:Protein Engineering
chemical_list: D000485:Allergens; D000939:Epitopes; D007073:Immunoglobulin E